Laboratory of Molecular Biochemistry and Cell Biology, Department of Biochemistry, ICMR-Rajendra Memorial Research Institute of Medical Sciences (RMRIMS), Patna, Bihar, India.
Laboratory of Molecular Biochemistry and Cell Biology, Department of Biochemistry, ICMR-Rajendra Memorial Research Institute of Medical Sciences (RMRIMS), Patna, Bihar, India.
Adv Parasitol. 2022;117:75-155. doi: 10.1016/bs.apar.2022.04.002. Epub 2022 Jun 30.
Trypanosomatids are mainly responsible for heterogeneous parasitic diseases: Leishmaniasis, Sleeping sickness, and Chagas disease and control of these diseases implicates serious challenges due to the emergence of drug resistance. Redox-active biomolecules are the endogenous substances in organisms, which play important role in the regulation of redox homeostasis. The redox-active substances like glutathione, trypanothione, cysteine, cysteine persulfides, etc., and other inorganic intermediates (hydrogen peroxide, nitric oxide) are very useful as defence mechanism. In the present review, the suitability of trypanothione and other essential thiol molecules of trypanosomatids as drug targets are described in Leishmania and Trypanosoma. We have explored the role of tryparedoxin, tryparedoxin peroxidase, ascorbate peroxidase, superoxide dismutase, and glutaredoxins in the anti-oxidant mechanism and drug resistance. Up-regulation of some proteins in trypanothione metabolism helps the parasites in survival against drug pressure (sodium stibogluconate, Amphotericin B, etc.) and oxidative stress. These molecules accept electrons from the reduced trypanothione and donate their electrons to other proteins, and these proteins reduce toxic molecules, neutralize reactive oxygen, or nitrogen species; and help parasites to cope with oxidative stress. Thus, a better understanding of the role of these molecules in drug resistance and redox homeostasis will help to target metabolic pathway proteins to combat Leishmaniasis and trypanosomiases.
利什曼病、昏睡病和恰加斯病，由于耐药性的出现，这些疾病的控制带来了严重的挑战。氧化还原活性生物分子是生物体内的内源性物质，在调节氧化还原平衡中发挥着重要作用。还原型谷胱甘肽、三肽巯基、半胱氨酸、半胱氨酸过硫化物等氧化还原活性物质和其他无机中间体（过氧化氢、一氧化氮）是非常有用的防御机制。在本综述中，描述了利什曼原虫和锥虫中三肽巯基和其他必需巯基分子作为药物靶点的适宜性。我们探讨了三肽还原酶、三肽还原酶过氧化物酶、抗坏血酸过氧化物酶、超氧化物歧化酶和谷氧还蛋白在抗氧化机制和耐药性中的作用。三肽巯基代谢中一些蛋白质的上调有助于寄生虫在药物压力（葡甲胺锑酸钠、两性霉素 B 等）和氧化应激下存活。这些分子从还原型三肽巯基接受电子，并将其电子捐赠给其他蛋白质，这些蛋白质还原有毒分子，中和活性氧或氮物质；并帮助寄生虫应对氧化应激。因此，更好地了解这些分子在耐药性和氧化还原平衡中的作用将有助于针对代谢途径蛋白来对抗利什曼病和锥虫病。
